The proposed research can be divided into two main aspects. The first concerns studies on the hepatitis B virus (HBV) life cycle. The aim of this work is a comprehensive understanding of the virus and how it functions to replicate itself in the hepatic cell. It includes (1) a comprehensive analysis of HBV genes (surface (HBsAg), core (HBcAg) antigens, DNA polymerase?, and a 750b RNA) and their expression in vivo and in vitro. In addition, we will determine the nature of the "e" antigen. (2) Analysis of presumed replicative forms of the virus and the cotnrol of replication of the virus. (3) The molecular characterization of the 22nm HBsAg particle. (4) A study of the molecular basis of hepatotropism--a search for a putative HBV receptor. (5 Development of an in vitro system for studying infectivity and vegetative growth of the virus. The second major aspect concerns an analysis of the role of HBV in disease. The aim of these studies is to elucidate the molecular basis of HBV induced hepatitis and to directly test whether HBV os tje causative agent of PHC. The proposal includes (1) studies of the various viral DNA forms andof virus-derived HBsAg particles in the liver and serum of infected patients--various forms of hepatitis (self limited hepatitis, fulminant hepatitis, chronic hepatitis, carriers), and in primary hapatocellular carcinoma (HPC). (2) Analysis of structure and expression of HBV sequences integrated in genomic DNA of hapatomas and the biochemical consequences of this integration. This may reveal the molevular outline of a basic ontological process. (3) Tests whether the expression of single or pairs of virus genes will cause cellular lesions. These studies will contribute to our knowledge of viruses and viral diseases. They may illuminate the etiology of the world's most prevalent cancer. In addition they will contribute undersanding of basic molecular details of gene structure, and regulation of gene expression in mammalian cells as well as the molecular specifics of host-tissue specificity.